Although serotonin (5-HT) is generally conceded to be one of the neurotransmitters which control pituitary-adrenocortical activity, uncertainty remains as to whether its action is predominantly excitatory or inhibitory (or both) in this system. Using systemically administered agonist drugs, some researchers have concluded that central serotonergic pathways normally promote pituitary ACTH secretion. Yet data from our laboratory show that such drugs are actually acting outside of the "blood-brain barrier." Thus 5-HT under these circumstances might be influencing the pituitary gland itself or exerting a primary effect on nonneuroendocrine tissues. A few brain regions such as the hypothalamic median eminence which lack the aforementioned permeability barrier must also be considered as potential sites of action. We propose 2 experiments to help resolve this dilemma. Both will entail the systemic administration to rats of quipazine (a direct 5-HT receptor stimulant) or fenfluramine (an acute 5-HT releasing agent), drugs already known to stimulate pituitary-adrenocortical secretion. Serial blood samples obtained from each subject via an indwelling jugular catheter will subsequently be assayed for corticosterone by radioimmunoassay. In the first study, animals will have been pretreated with the potent 5-HT neurotoxin 5,7-dihydroxy-tryptamine in order to destroy serotonergic innervation of the hypothalamus and possibly also the pituitary. The second study will utilize rats bearing extensive basomedial hypothalamic lesions, thereby dissociating pituitary ACTH secretion from the normal control of corticotropin-releasing-factor. Together, these 2 approaches will separate the potential contributions of hypothalamic, pituitary, and peripheral actions of systemically administered serotonergic drugs. The results should have an important clinical impact regarding the use of such drugs in the treatment of certain adrenal endocrinopathies such as Cushing's disease.